Download - Adrenergic agonists & antagonists
Adrenergic Agonists & Antagonists
Brian J. Piper, Ph.D., M.S.
Objective
• Describe the main uses and adverse effects of selective & non-selective adrenergic agonists
• Describe the main uses and adverse effects of adrenergic antagonists
Tom WestfallDavid Westfall
Sympathetic “Fight or Flight”
Parasympathetic “Rest & Maintain”
RestRepairRenew
*
* Acetylcholine & muscarinic receptors for sweat glands
Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology, p. 56.
Jargon
sympathomimetic: drug that activates sympathetic nervous systemparasympathomimetic: drug that activates parasympathetic nervous systemsympatholytic: drug that decreases or blocks sympathetic responseparasympatholytic: drug that decreases or blocks parasympathetic responseadrenaline = epinephrine
Drugs that affect Autonomic Nervous System will affect:
• Heart• Blood Vessels• Bowels• Pancreas• Ureters• Bladder
• Eyes• Pupils• Lacrimal Gland• Salivary Glands• Lung Airways• Brain
Where are the adrenergic receptors?
Receptor: α1 α2 β1 β2 β3
localization blood vessels
pancreas heart lungs adiposetissue
vas deferens g.i. tract kidney g.i. tract
uterus (pregnant)
CNS uterus (non-pregnant)
adipose tissue
ureter stomach salivary glands
Adrenergic Projections (CNS)
Pronunciation: http://www.merriam-webster.com/cgi-bin/audio.pl?locusc03.wav=locus+coeruleushttp://dictionary.reference.com/browse/peduncle?s=t
brain stemspinal cordcerebellumfrontal cortexlimbic system
Brodal (2010). Central Nervous System. p. 377.
Functional Localization
Descending Projections Ascending Projections
β1
α1
Stahl, S. (2000). Essential Psychopharmacology, p. 165-167.
Adrenergic Neurotransmission (CNS)
Postsynaptic: α1, α2, β1Presynaptic: α2
Stahl, S. (2000). Essential Psychopharmacology, p. 160-161.
Pheochromocytoma
• Tumor of chromaffin cells of adrenal medulla (4:1 NE to Ep)
• Symptoms– ↑ heart rate– ↑ blood pressure/orthostatic blood pressure– ↑ anxiety– ↓ weight– diaphoresis
cortex
medulla
http://www.learningradiology.com/archives2011/COW%20441-Pheochromocytoma/pheocorrect.htm
“selective” ≈ 50-100 fold
Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 278.
Phenylephrine• Mechanism: selective α1 agonist,
vasoconstriction• Uses:– decongestant: substitute for pseudoephedrine but
controversy (at 10 mg, oral) over effectiveness1
– postural hypotension: ↑blood pressure without cardiac effects, concern: supine hypertension
– detumescent (urologist)
1Hendeles, L. (2006) Oral phenylephrine: An ineffective replacement for pseudoephedrine? J Allergy Clin Immunology, 118(1), 279-280.
Epinephrine
Clonidine• Mechanism: neural pre-synaptic α2 agonist (?) • Uses: mild hypertension
Zhou et al. (1999). British Journal of Pharmacology, 126, 1522-1530.
129SV mouse
Wild-type α2A Knock-Out
Clonidine• Mechanism: neural pre-synaptic α2 agonist (?) • Uses: mild hypertension
Zhou et al. (1999). British Journal of Pharmacology, 126, 1522-1530.
129SV mouse
Wild-type α2A Knock-Out
Clonidine• Mechanism: neural pre-synaptic α2 agonist• Uses: mild hypertension, ADHD• Side-Effects: dry mouth & sedation (↓), sexual
β Adrenergic AgonistsDrug Mechanism Use(s) Adverse Effects
Isoproterenol1 β1β2 agonist bradycardia (emergency )
palpitations, headaches, tachycardia, flushing
Dobutamine β1 agonistα1 agonist/α1 antagonist
congestive heart failure (short-term)
↑ size of myocardial infarct↑ risk of arrhythmia
Albuterol β2 agonist bronchospasm(short-term)
anxiety, headache, dry-mouth
Salmeterol β2 agonist bronchospasm(long-term)
upper respiratory tract inflammation
Formoterol β2 agonist bronchospasm nasopharyngitis, headache
1Pronunciation: http://dictionary.reference.com/browse/Isoproterenol?s=ts
References: G & G; Lippincott’s; pdr.net
Comparison of β Agonists for Asthma
Safety of Long-Acting β-agonists for Asthma
• A large trial (N=26,000) found a 4-fold elevation in asthma related deaths with salmeterol1.
• Deaths are uncommon (2/1000 patient-years)• Prior research on more frequent outcomes has
been revealed inconsistent results• What to do?– Tally studies (worst)– Authority (ok)
1Salmeterol Multi-center Asthma Research Trial (SMART)
Meta-Analysis of LABA Asthma Related Hospitalizations
Odds Ratio = 1 means probability of event is equal in both groupsOdds Ratio <> 1 means probability of event differs in each groupOR salmeterol = 1.7, OR formoterol = 3.2; OR children = 3.9, OR adults = 2.0
Salpeter et al. (2006). Annals of Internal Medicine, 144, 904-912.
->
Long Acting B Agonists FDA Warning
http://www.pdr.net/drugpages/concisemonograph.aspx?concise=1691
Neuroanatomy of Food Intake
Meyer & Quezner (2005). Psychopharmacology. p. 135.
Hypothalamus1) Lateral: hunger center “gas”2) Ventro-medial: satiety center “brakes”
1 2
Norepinephrine & Food Intake
Meyer & Quezner (2005). Psychopharmacology. p. 135.
α1 & β12 Agonists & Arousal
Meyer & Quezner (2005). Psychopharmacology. p. 134; from Berridge et al. (2004). Brain Research Review, 42, 33-84.
30 Minute Blocks
Phenylephrine (10 x 10-9 mol), isoproterenol (4 x 10-9 mol) or both injected into the medial septum. Behavior based on EEG/EMG.
Ephedrine• Ephedra sinica (má huáng) used in traditional
Chinese medicine• Contains ephedrine and pseudoephedrine• Mixed: α1 α2 β1 β2 agonist, NE releaser• 2002: FDA withdrawal from OTC diet agents
over concerns of strokes & arrhythmias (but gone?)
Kaplan (2011). Gastroenterology Clinics North America, 39(1), 69-79.
Ephedra & Weight Loss: Example Randomized Controlled Trial
• Overweight (BMI > 25) participants were randomized to placebo or ma huang/kola pills (tid)
• Analytical chemistry revealed 33 mg ephedrine & 14 mg caffeine
• Ambulatory monitoring revealed slight changes (BP: Placebo -3; Herbal +4)
• Adverse effects: insomnia & anxiety• Weight loss but:
– placebo response– drop-out
Boozer et al. (2002). International J Obesity, 26, 593-604.
History of Methamphetamine• 1893: Synthesized by Nagai Nagayoshi in Japan• 1940s- : Popular with military• 1960s- : used for short-term treatment of obesity, narcolepsy,
and, later, ADHD• 1983-2005 : state and federal laws attempt to reduce use by
decreasing availability of ephedrine and pseudoephedrine• 2000s- : several aggressive (factually correct?) advertising
campaigns are aimed at reducing demand
History of Methamphetamine• 1960s- : used for short-term treatment of obesity, narcolepsy,
and, later, ADHD• 1983-2005 : state and federal laws attempt to reduce use by
decreasing availability of ephedrine and pseudoephedrine• 2000s- : several aggressive (factually correct?) advertising
campaigns are aimed at reducing demand
Starts slow (3 min): http://montana.methproject.org/Our-Work/brain-and-behavior.php
True or False: “the MMP results in Montana have been more significant than any other drug prevention program in history”?
Youth Risk Behavior Survey
• High School students were asked about lifetime methamphetamine use before and after the Montana Methamphetamine Project.
Anderson (2010) J Health Econ, 29, 732-742.
Positron Emission Tomography of the Dopamine Transporter
PD = Parkinson’s Disease
Montana Meth Project
• Businessman Thomas Siebel supported graphic advertising in 2005
• Goal was to reach each teenager 3+ times/week (TV, radio, print).
To View Ads: http://www.montanameth.org/View_Ads/index.php
Similarities & Differences of Exposed & Unexposed Children
Unexposed (N=35) Exposed (N=31)
Trimesters of Methamphetamine 0 (0) 2.5 (0.3)***
Income while pregnant : <15,000Income currently : >35,000
17.1%51.4%
76.2*60.0%
Maternal Age at Birth (years) 26.9 (1.1) 29.8 (1.5)
Nicotine 17.1% 76.2***
Alcohol 11.4% 71.4%***
Marijuana 11.4% 58.8%*
Biological father involved 85.7% 44.8%***
Number of other childrenIn home
2.7 (0.3) 1.3 (0.3)**
Piper et al. (2011). Pharmacol Biochem Behav, 98, 432-439.
p < *.05, **.01, or ***.005
Behavioral Rating Inventory of Executive Function (BRIEF)
• Please rate whether the following behaviors are never, sometimes, or often a problem (1-3 points):– Emotional Control (EC) : overreacts to small problems– Inhibit (INH): interrupts others– Shift (SHI): becomes upset with new situations– Working Memory (WM): when given three things to do, remembers only the first or last– Initiate (INI): has trouble coming up with ideas for what to do in play time– Plan/Organize (PO): gets caught up in details and misses the big picture– Organization of Materials (OM): cannot find things in room– Monitor (MON): does not check work for mistakes– Behavioral Regulation Index + Metacognition Index =
Global Executive Composite (Mean= 50.0, SD = 10)
Gioia GA, Isquith PK, Guy SC, et al. (2000). Behavioral Rating Inventory of Executive Function: Professional Manual. Psychological Assessment Resources: Lutz.
*** p < .0005, ** p < .005, * p < .05
“Clinically Significant” Behavioral Problems in Children Exposed Prenatally to Methamphetamine & Other Drugs
Piper et al. (2011). Pharmacol Biochem Behav, 98, 432-439.
Common Sympathomimetic Drugs
Drug Schedule FDA ApprovedFor
AcuteMechanisms
High-Dose
methamphetamine(Desoxyn)
II ADHDobesity
Per: αβ agonistCen: DA, NE, 5-HT
↓DAT↓ SERT
amphetamine(Adderall)
II ADHDnarcolepsy
Per: αβ agonistCen: DA, NE, 5-HT
↓DAT
Methylphenidate(Ritalin)
II ADHDnarcolepsy
Per: αβ agonistCen: DA, NE
Cen = central nervous system; Per = peripheral nervous system
Top Drug Molecules Dispensed to the Pediatric Population From US Retail Pharmacies According to Patient Age in 2010
Chai et al. (2012). Pediatrics, 131(1), 23-31. Grace Chai, PharmD
Weight, Growth, & Psychostimulants
• statistically but clinically significant?
• height ≈ 0.5 cm/year• weight ≈ 2 kg/year• tolerance• catch-up?
Faraone et al. (2008). Journal of the American Academy of Child & Adolesclent Psychiatry, 47(9), 994-1009.
Cocaine
• Mechanism: – Central: block DAT, NET & SERT– Peripheral: αβ agonist
• Schedule II (nasal surgery)
Erythroxylon coca powder crack
Why is cocaine reinforcing?
Meyer & Quenzer (2008). Psychopharmacology. p. 283; Rocha (2003). Eur J Pharmacol, 479, 107-115.
C57 mouse
Why is cocaine reinforcing?
Meyer & Quenzer (2008). Psychopharmacology. p. 283; Rocha (2003). Eur J Pharmacol, 479, 107-115.
Drug Abuse Warning Network• Tracks number of time drug is
implicated in (urban) ER visits• poly-substance use
Drug N
alcohol 17,796
cocaine 11,431
heroin 10,493
opiates (oxycontin) 8,525
antidepressants 1,875
stimulants (meth, amph) 739
Boston 2010
http://www.samhsa.gov/data/DAWN.aspx#DAWN%202010%20ED%20Excel%20Files%20%E2%80%93%20Metro%20Tables
<- Thalamic hemorrhage in crack smoker (CT)
Reserpine
• component of Rauwolfia serpentina (Indian snakeroot)• mechanism: long-term VMAT inhibitor• effects– ↓ blood pressure– depression– sedation
Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 304.
Yohimbine
• Content of African tree bark• Pre-synaptic α2 antagonist• Inconsistent bioavailability (5 to 80%)• Purported male aphrodisiac (ED)
Pausinystalia yohimbe
β Blockers Overview
• End in “olol”• Contraindications: asthma• Heart, eyes, kidneys (β1 predominate)
• Lungs, smooth muscle, uterine muscle (β2 predominate)
O to 4:00 (skip add): http://www.youtube.com/watch?v=h2QR8HxxY1I
Controversy Over Phenylephrine
Hendeles, L. (2006) Oral phenylephrine: An ineffective replacement for pseudoephedrine? J Allergy Clin Immunology, 118(1), 279-280.
Terminology Refresherpositive ionotropic action (p. 282): increased strength of ventricular contractionpositive chronotropic action (p. 282): increased rate of heart contractionhyperhidrosis (p. 296): excessive sweating
General Refresher 0 to 31:50: http://www.youtube.com/watch?v=bMnz7dgHztg&feature=related